Opioid agonists are the mainstay of analgesic therapy and constitute maintenance therapy for the management of opiate dependence. These drugs, in addition to illicit forms such as heroin, are also among the most widely abused. By compensating for tolerance with dose escalation, dependence can develop, and harmful side-effects become a liability. Among the mechanisms underlying cellular tolerance is an uncoupling of opioid receptors from effectors such that greater receptor occupancy is required to obtain a given response. This process is similar to mu-opioid receptor (MOR) desensitization. Importantly, acute MOR regulation - desensitization, interalization, recovery - occurs in a highly agonist-specific manner. The goals of this proposal are to (1) determine the degree of tolerance induced by the chronic treatment of rats with 3 commonly used opioids: morphine, methadone and buprenorphine; (2) investigate how chronic treatment with these agonists changes the induction and recovery from acute MOR desensitization; (3) determine the acute pharmacological properties of buprenorphine. It is hypothesized that chronic treatment with these three agonists will result in electrophysiologically distinguishable effects on MOR regulation. [unreadable] [unreadable] [unreadable]